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WO2010047774A2 - Inhibiteurs de la mycobacterium tuberculosis malate synthase, procédés de marquage et utilisations de ceux-ci - Google Patents

Inhibiteurs de la mycobacterium tuberculosis malate synthase, procédés de marquage et utilisations de ceux-ci Download PDF

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Publication number
WO2010047774A2
WO2010047774A2 PCT/US2009/005697 US2009005697W WO2010047774A2 WO 2010047774 A2 WO2010047774 A2 WO 2010047774A2 US 2009005697 W US2009005697 W US 2009005697W WO 2010047774 A2 WO2010047774 A2 WO 2010047774A2
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Prior art keywords
malate synthase
compound
substituted
alkyl
nmr
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WO2010047774A3 (fr
Inventor
Joel S. Freundlich
James C. Sacchettini
Inna V. Kriger
Thomas R. Ioerger
Vijay Gawandi
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Texas A&M University System
Texas A&M University
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Texas A&M University System
Texas A&M University
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Publication of WO2010047774A2 publication Critical patent/WO2010047774A2/fr
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    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/527—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving lyase

Definitions

  • the present invention relates generally to the fields of tuberculosis treatment, enzymology and drug screening. More specifically, the present invention relates to substituted aryl- and heteroaryldiketo acids and derivatives thereof as therapeutics in the treatment of tuberculosis, particularly persistent tuberculosis, and their design.
  • Mtb Mycobacterium tuberculosis
  • Mtb is an airborne threat that can be spread by coughs, sneezes, and even droplets from normal speech. In areas of high population density, TB can be spread very rapidly. TB infection rates are on the rise due in part to the HIV epidemic, as there is a synergistic relationship between HIV and TB, where both diseases progress much faster in the co-infected individual. TB has become the leading cause of death for people with HIV (13% of deaths worldwide).
  • Chemotherapy for TB now uses a treatment of multiple antibiotics, e.g., isoniazid, pyrazinamide, ethambutol, and rifampin, that lasts between 6 to 12 months for drug sensitive infection.
  • antibiotics e.g., isoniazid, pyrazinamide, ethambutol, and rifampin
  • One major obstacle in combating Mtb during the course of the treatment is the bacteria's ability to survive for extended periods of time in the body in a non-replicative state, referred to as the persistent phase of infection.
  • the bacteria are characterized as being recalcitrant to treatment by conventional anti-TB drugs and are able to evade the host immune response. This phenotypic resistance dictates the requirement for prolonged drug treatments and oftentimes results in patient non-compliance.
  • Asymptomatic latent infection Another threat to the global control of TB is the asymptomatic latent infection.
  • Asymptomatic infections can be activated unpredictably, especially if the patient becomes immunocompromised.
  • the degree of similarity in the metabolic state between bacilli in the persistent and latent phases is not known. However, it is this inherent aspect of the bacteria - its ability to survive in the body for extended periods of time- which reduces the efficacy of current treatments.
  • Drug-resistant strains to at least one TB drug have been found in every country in the world. Many factors contribute to the rise of drug resistance, including low compliance with therapy regimens, poor quality or counterfeit drugs, improper use of drugs, and inadequate health care systems.
  • glyoxylate shunt enzymes isocitrate lyase (ICL) and malate synthase have been implicated as virulence or persistence factors in several different pathogens.
  • ICL isocitrate lyase
  • malate synthase Two genes of the glyoxylate shunt, icll and mis], encoding isocitrate lyase and malate synthase, respectively, were induced upon phagocytosis of Candida albicans by macrophages. A mutant of C.
  • albicans lacking icll was less virulent in mice than wild-type.
  • the glyoxylate pathway has also been implicated in the pathogenesis of Brucella abortus and Rhodococcus equi, as well as in the virulence of the plant pathogens Rhodococcus fascians and Stagonospora nodorum.
  • Mtb For Mtb, it has been reported that genes encoding both of the enzymes are up- regulated in response to phagocytosis.
  • An icll null strain of Mtb is able to establish an acute infection in mice, but is not able to sustain the chronic, persistent infection seen in mice infected with wild-type Mtb.
  • the anaplerotic maintenance of the tricarboxylic acid (TCA) cycle is afforded by the glyoxylate shunt during conditions where the generation of pyruvate from glycolysis is reduced and beta-oxidation of fatty acids provides the major source of carbon. This metabolic perturbation is vital to the survival of the bacteria.
  • Beta-Oxidation of fatty acids results in increased levels of acetyl CoA, which gets incorporated into isocitrate.
  • ICL converts isocitrate to glyoxylate and succinate.
  • the next enzyme in the glyoxylate cycle malate synthase, condenses glyoxylate and acetyl CoA to produce malate.
  • An advantage of the glyoxylate cycle, during conditions where beta-oxidation is high, is the bypass of the CO 2 - generating steps of the TCA cycle.
  • the glyoxylate shunt When working in concert with the TCA cycle, the glyoxylate shunt will replenish the concentration of two intermediates, succinate and malate, which will have the overall effect of maintaining oxaloacetate levels (as the entry point for acetyl CoA in the TCA cycle).
  • malate synthase In the Mtb genome, a single malate synthase gene (called glcB or mlsl) encodes a malate synthase isoform (malate synthase G, Rvl837c).
  • Malate synthase is an 80 kDa (741 amino acids) monomeric protein, homologous to malate synthase (AceB) of the gram-positive bacterium Corynebacterium glutamicum (Reinborg et al. 1994) and the gram- negative Escherichia coli, with ⁇ 60% sequence identity. Functional properties of malate synthase from Mtb have been studied as well. The specific activity of the purified enzyme was 6 ⁇ mol/min/mg protein.
  • the K n , of the recombinant protein was determined to be 57 ⁇ M for glyoxylate and 30 ⁇ M for acetyl CoA. In the absence of divalent cations only negligible activity was measured for the purified enzyme. Mg +2 at 5 mM was found to be the most effective cation. Mn +2 was able to replace Mg +2 , yielding 40% of the activity obtained with Mg +2 . Co +2 , Fe +2 , Ca +2 , Ba +2 , Ni +2 , Cd +2 , Zn +2 , Cu t2 , and Hg +2 were unable to support significant activity. The optimal pH for malate synthase activity was found to be 7.5. (Smith et al. 2003).
  • Oxalate, phosphoenolpyruvate, and bromopyruvate were the most potent inhibitors with inhibition constants of 400, 200, and
  • tuberculosis drugs effective to treat persistent strains of Mycobacterium tuberculosis.
  • the prior art is deficient in novel substituted aryl- and heteroaryldiketo acids and derivatives thereof in the treatment of tuberculosis.
  • the present invention fulfills this long-standing need and desire in the art.
  • the present invention is directed to a substituted diketo acid compound having the chemical structure comprising: wherein R 1 is a phenyl, a naphthyl, a thienyl, bithiophenyl, imidazolyl, benzothienyl, furanyl, benzofuranyl, pyrimidinyl, pyrrolyl, or pyridyl or substituted derivatives thereof; and R 2 is H, OH, OCi -6 alkyl, NH 2 , NHC ⁇ alkyl, or N(C, ⁇ alkyl) 2 ; or a pharmacologically acceptable salt thereof.
  • a pharmaceutical composition comprising the aryl diketo acid compounds described supra and a pharmaceutically acceptable carrier.
  • the present invention also is directed to a substituted diketo acid comprising compounds listed in Example 3.
  • the present invention is directed further to a method for inhibiting an activity of a malate synthase enzyme in a bacterium, for example a Mycobacterium.
  • the method comprises contacting the bacterium with an effective amount of one or more of the aryl diketo acid compounds described herein.
  • the present invention is directed further still to a method for treating tuberculosis in a subject.
  • the method comprises administering one or more times a pharmacologically effective amount of one or more of the aryldiketo acid compounds described herein.
  • the present invention is directed to a related method comprising a further step of administering one or more times a pharmacologically effective amount of one or more other tuberculosis drugs.
  • the present invention is directed further still to a method for treating a pathophysiological condition caused by a bacterium having a malate synthase activity in a subject.
  • the method comprises administering one or more times a pharmacologically effective amount of one or more of the aryldiketo acid compounds described herein.
  • the present invention is directed to a related method comprising a further step of administering one or more times a pharmacologically effective amount of one or more other drugs effective to treat the pathophysiological condition.
  • the present invention is directed further still to a method for designing a potential inhibitory compound of a Mycobacterium malate synthase enzyme.
  • the method comprises identifying a compound in silico that interacts with the malate synthase active site screening the potential compound for inhibition of CoA production by Mycobacterial malate synthase. The identification is based at least in part on a computer model of a crystalline structure of the malate synthase enzyme.
  • the present invention is directed to a related method comprising the further step of measuring growth inhibition of a Mycobacteria culture in the presence of the screened inhibitory compound compared to growth of a control in the absence thereof.
  • the present invention is directed further still to an inhibitory compound designed by the method described herein.
  • the present invention is directed further still to a three-dimensional X-ray crystal structure comprising a Mycobacterial malate synthase complexed to an inhibitory compound designed by the method described herein.
  • the present invention is directed further still to a method for increasing the stability of an aromatic or heteroaromatic diketo acid compound in solution.
  • the method comprises derivatzing the aromatic ring or heteroaromatic ring comprising the diketo acid or a prodrug thereof in at least an ortho position with a substituent effective to disrupt coplanarity of the aromatic or heteroaromatic ring with the diketo acid moiety thereby stabilizing the aromatic or heteroaromatic diketo acid compound.
  • Figure 1 is a gel depicting purification of the truncated form of Mtb malate synthase.
  • Lane 6 is markers; lanes 7-18 are fractions from a gel filtration column showing greater than 95% pure malate synthase (80 kDa).
  • Figure 2 depicts the active site of malate synthase in complex with CoA and malate.
  • Figure 3 shows the superposition of docked conformation of 4-phenyl-2,4- diketobutanoic acid (PKBA).
  • Figure 4 is the general chemical synthetic scheme for a phenyl -substituted diketo acid.
  • Figure 5 is a high-resolution crystal structure of wild-type GIcB depicting phenyl keto butanoic acid contacts with the GIcB active site.
  • Figures 6A-6C show the superposition of docked ortho-substituted ( Figure
  • Figure 7 illustrates the correlation between absorbance peaks and stability in solution in selected phenyl-substituted or napthyl keto butanoic acid derivatives and analogs.
  • the term “compound” is interchangeable with “inhibitor”, or “inhibitory compound” and means a molecular entity of natural, semi-synthetic or synthetic origin that blocks, stops, inhibits, and/or suppresses substrate interactions with a Mycobacterial malate synthase, particularly the formation of CoA from acetyl CoA.
  • inhibit refers to the ability of the compound to block, partially block, interfere, decrease, reduce or deactivate a Mycobacterial or other bacterial malate synthase enzyme or protein.
  • inhibit encompasses a complete and/or partial loss of activity of a malate synthase.
  • a complete and/or partial loss of activity of the malate synthase may be indicated by a reduction in production of CoA, a reduction in mycobacterial cell proliferation, or the like.
  • the term "contacting” refers to any suitable method of bringing one or more of the compounds described herein or other inhibitory agent into contact with a Mycobacterial or other bacterial malate synthase protein or polypeptide or fragment thereof or a Mycobacterium or other bacterium comprising the same. In vitro or ex vivo this is achieved by exposing the malate synthase protein or polypeptide or fragment thereof or cells comprising the same to the inhibitory agent in a suitable medium. For in vivo applications, any known method of administration is suitable as described herein. As used herein, the terms “effective amount” or “pharmacologically effective amount” are interchangeable and refer to an amount that results in an improvement or remediation of the disease, such as tuberculosis.
  • the effective amount may improve the patient's or subject's condition, but may not be a complete cure of the disease and/or condition.
  • the terms “treating” or “treatment” includes prophylactic treatment as well as alleviation of ongoing or intermittent symptoms occurring in a tuberculosis or persistent tuberculosis or other bacterial infection.
  • substituted diketo acid compound having the chemical structure comprising: wherein R 1 is a phenyl, a naphthyl, a thienyl, bithiophenyl, imidazolyl, benzothienyl, furanyl, benzofuranyl, pyrimidinyl, pyrrolyl, or pyridyl or substituted derivatives thereof; and R 2 is H, OH, OC 1-6 alkyl, NH 2 , NHC ⁇ alkyl, or N(C, ⁇ alkyl) 2 ; or a pharmacologically acceptable salt thereof.
  • a pharmaceutical composition comprising the substituted diketo acid compounds described supra and a pharmaceutically acceptable carrier.
  • R' may be a phenyl substituted with one or more of R 3 at C2, R 4 at C3, R 5 at C4, R 6 at C5, or R 7 at C6 or a 1- or 2-naphthyl substituted with one or more of R 3 at C3, R 4 at C4, or R 5 at C5.
  • R 3 , R 4 , R 5 , R 6 , and R 7 independently may be H, OH, NO 2 , C ⁇ alkyl, C ⁇ alkoxy, O(C,. 6 alkyl)O(C,.
  • R 3 , R 4 , R 5 , R 6 or R 7 independently may be methoxy, Br, F, Cl, I, or methyl and R 2 may be OH or 0C,_ 6 alkyl.
  • R 1 may be 1- or 2-naphthyl
  • R 2 may be OH or OC 1-6 alkyl
  • R 3 and R 4 may be H
  • R 5 may be OC 1-6 alkoxy.
  • R 1 may be a 2- or 3-thienyl or (3- methyl)-2-thienyl substituted with of R 8 at C5, wherein R 8 is p-R 3 Ph, phenoxyphenyl, or 2- thienyl.
  • the present invention provides a method for inhibiting an activity of a malate synthase enzyme in a bacterium, comprising contacting a bacterium with an effective amount of one or more of the aryldiketo acid compound as described supra.
  • the bacterium may be a Mycobacterium.
  • An example is Mycobacterium tuberculosis.
  • the present invention provides a method for treating tuberculosis in a subject, comprising administering one or more times a pharmacologically effective amount of the inhibitor described supra to the subject.
  • the method comprises administering one or more times a pharmacologically effective amount of one or more other tuberculosis drugs.
  • the other tuberculosis drugs may be isoniazid, rifampfin, pyrazinamide,or ethambutol.
  • the other tuberculosis drugs may be administered concurrently or consecutively.
  • the present invention provides a method for treating a pathophysiological condition caused by a bacterium having a malate synthase activity in a subject, comprising administering one or more times a pharmacologically effective amount of the inhibitor described supra to the subject. Further to this embodiment the method comprises administering one or more times a pharmacologically effective amount of one or more other drugs effective to treat the pathophysiological condition.
  • the pathophysiological condition may be tuberculosis and the other drugs are isoniazid, rifampicin, pyrazinamide.or ethambutol. Also in this further embodiment the other drugs may be administered concurrently or consecutively.
  • a method for designing a potential inhibitory compound of a Mycobacterium malate synthase enzyme comprising identifying a compound in silico that interacts with the malate synthase active site, the identification based at least in part on a computer model of a crystalline structure of the malate synthase enzyme. Further to this embodiment the method comprises screening the potential compound for inhibition of CoA production by Mycobacterial malate synthase.
  • the screening steps may comprise contacting a Mycobacterial malate synthase in the presence of an acetate carbon source with the potential compound and measuring production of CoA in the presence and absence of the potential compound; wherein a decrease in a level of CoA production in the presence of the compound compared to a level in the absence of the compound indicates that the potential compound is an inhibitor of the malate synthase.
  • the method comprises measuring growth inhibition of a Mycobacteria culture in the presence of the screened inhibitory compound compared to growth of a control in the absence thereof.
  • the potential compound may comprise a carboxylate moiety positioned to contact a Mg2+ ion comprising the malate synthase active site.
  • the potential compound may comprise a ketoacid positioned to bind a Mg2+ ion and a 1,3-diketo moiety positioned to form one or more hydrogen bonds with an amino acid residue functionally equivalent to a Arg-339 residue of native Mycobacterium tuberculosis malate synthase, both of the a Mg2+ ion and the functionally equivalent residue comprising the malate synthase active site.
  • the functionally equivalent amino acid residue is the native Arg-339 amino acid residue.
  • the potential compound may comprise a substituted phenyl moiety positioned to overlap an acetyl CoA binding site within the malate synthase.
  • a representative Mycobacterium is Mycobacterium tuberculosis.
  • the present invention provides an inhibitory compound designed by the screening method as described supra.
  • the present invention provides a three-dimensional X-ray crystal structure comprising a mycobacterial malate synthase complexed to an inhibitory compound designed by the screening method as described supra.
  • a method for increasing the stability of an aromatic or heteroaromatic diketo acid compound in solution comprising derivatzing the aromatic ring or the heteroaromatic ring comprising the diketo acid or a prodrug thereof in at least an ortho position with a substituent effective to disrupt coplanarity of the aromatic or heteroaromatic ring with the diketo acid moiety thereby stabilizing the aromatic or heteroaromatic diketo acid compound.
  • aromatic ring is a phenyl or naphthyl moiety and the heteroaromatic ring is a thienyl moiety.
  • the stabilizing substituent may be OH, NO 2 , C ⁇ alkyl, C ⁇ alkoxy, O(C ⁇ alkyl)O(C, ⁇ alkyl), Br, F, Cl, I, Ph, PhCH 2 , PhOCH 3 , Ph(CH 2 ) 2 , CF 3 , CH 3 SO 2 , or imidazolyl.
  • the stabilized aromatic or heteroaromatic diketo acid compound inhibits an activity of a bacterial malate synthase upon contact therewith in vitro or in vivo.
  • a representative bacterium is a Mycobacterium.
  • the well-defined and characterized active site of malate synthase exhibits little conformational change upon substrate binding, thus making it an attractive target for structure-based design.
  • the vital importance of the glyoxlate shunt in persistent bacteria supports the contention that a malate synthase inhibitor could lead to a novel anti-tubercular drug able to control persistent tuberculosis. It is contemplated that the inhibitory compounds and methods provided herein enable a dramatic shortening of TB regimens leading to a better drug therapies and a significant reduction in the outgrowth of drug-resistant TB.
  • inhibitors of mycobacterial malate synthase enzyme are aromatic, heterocyclic, aryl, or heteroaryl substituted diketo acids, for example an analog or derivative of phenyl keto butanoic acid (PKBA).
  • PKBA phenyl keto butanoic acid
  • R 1 may be, but not limited to, aryl groups, such as substituted phenyl groups or a 1- or 2-naphthyl group which may be substituted at one or more of C6- C8.
  • R 1 structures are: or
  • the R 2 substituent determines if the compound is the diketo acid or the ester, ketone, amide or substituted amide, or aldehyde derivative thereof.
  • R 2 may be, although not limited to, a hydrogen, hydroxyl, an alkoxy or the amide or the C 1-6 alkyl mono- or di-substituted amide.
  • the R 3 -R 5 substituents independently may be a hydrogen, a nitro group, straight or branched-chained alkyl, a halide, an C 1 ⁇ alkoxy or a C 1-6 dialkoxy, a phenyl or a substituted phenyl.
  • the alkyl chain may be a C w moiety, such as methyl, ethyl, n- or iso-propyl, or a butyl group.
  • the halide may be a fluorine, a bromine, a chlorine, an iodine, or a tritluoromethyl.
  • the phenyl substituent may be substituted with one or two methylenes.
  • the naphthyl substituents may be 1- or 2-naphthyl and may be substituted with R 3 -R 5 at C8, C7 and C6, respectively.
  • R' may be a heterocycle or heteroaryl, such as, but not limited to a thiophene, preferably a 2- or 3-thienyl, which may be substituted at C5 with an R 8 substituent.
  • R 1 structures may be
  • the R 8 substituents may comprise a phenyl s ubstituted w re of R 3 , R 4 , R 5 , R 6 , R 7 substituents or a heterocycle or other heteroaryl moiety, such as, but not limited to, a phenoxyphenyl or methylfuranyl.
  • Other heterocyclic R 1 substituents comprise a bithiophenyl, imidazolyl, benzothienyl, furanyl, benzofuranyl, pyridinyl, or pyrrolyl which may be further substituted at available carbons with those substituents as on the phenyl, naphthyl, or thienyl moieties.
  • these aryl- or heteroaryl -diketo acid compounds may be formulated as a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers are well-known and standard in the art. Without being limiting, such carriers refer to a non-toxic, inert solid, semi-solid liquid filler, diluent, encapsulating material, formulation auxiliary of any type, or simply a sterile aqueous medium, such as saline.
  • an aromatic or heteroaromatic diketo acid or a prodrug or close analog of the diketo acid such as, but not limited to, phenyl keto butanoic acid, naphthyl keto butanoic acid or thienyl keto butanoic acid or carboxylate derivatives thereof.
  • derivatizing the aromatic or heteroaromatic moiety at least at an ortho or equivalent position on the ring perturbs the relative orientation of the ring with the diketoacid moiety thereby disfavoring a retro-Claisen decomposition of the aromatic or heteroaromatic diketo acid.
  • the phenyl keto butanoic acid diketo acid derivatives and analogs provided herein are generally synthesized by condensing the aryl methyl ketone with a suitable dialkyloxalate with subsequent hydrolysis of the formed aryl diketoacid alkyl ester (see Example 2).
  • Prodrugs of the aromatic or heteroaromatic diketo acids may be formed by standard chemical and/or biotechnological methods known in the art.
  • inhibitors for malate synthase could be quite effective tools for elucidating and gaining deeper insights in the role this enzyme plays in the various physiological states of the organism. It has been very difficult to study bacteria in the persistent and latent infections because they are composed of bacilli in a dormant non-dividing state. In tact, it is not yet clear what the relationship is between persistent and latent bacilli. It is yet another object of the present invention to validate malate synthase as a drug target for the all stages of tuberculosis infection, i.e., acute, chronic or persistent phase of a Mycobacterium tuberculosis (Mtb) infection.
  • Mtb Mycobacterium tuberculosis
  • the effective amount of the malate synthase inhibitor or related-compounds thereof to be used are those amounts effective to produce beneficial results in the recipient subject or patient. Such amounts may be initially determined by reviewing the published literature, by conducting in vitro tests or by conducting metabolic studies in healthy experimental animals. Before use in a clinical setting, it may be beneficial to conduct confirmatory studies in an animal model, preferably a widely accepted animal model of the particular disease to be treated. Preferred animal models for use in certain embodiments are rodent models, which are known and standard in the art.
  • a specific dose level of active compounds such as a malate synthase inhibitor or a related-compound(s) thereof for any particular subject or patient depends upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy. The person responsible for administration will determine the appropriate dose for the individual subject. Moreover, for human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards.
  • the effective amount of the malate synthase inhibitor or a related-compound thereof can be the amount that is required to achieve the desired result, that is, although not limited to, reduction/inhibition in production of CoA from acetyl CoA.
  • Administration of the therapeutic malate synthase inhibitor composition of the present invention to a patient or subject will follow general protocols for the administration of therapies used in treatment of tuberculosis, particularly persistent tuberculosis, taking into account the toxicity, if any, of the malate synthase inhibitor. It is expected that the treatment cycles would be repeated as necessary. It also is contemplated that various standard therapies may be applied in combination, such as concurrent or consecutive co-administration, with the described therapy. Current and standard anti -tubercular drugs include, but are not limited to, isoniazid, rifampicin, pyrazinamide.or ethambutol. It is further contemplated that routes of administration may be those well-known and standard for treatment of tuberculosis. Alternatively, it is well within the ordinary skill of one in this field to determine an effective route of administration of the inhibitory compounds provided herein.
  • the inhibitory compounds provided herein are effective to inhibit an activity of malate synthase in a bacterium other than a Mycobacterium.
  • the bacteria have a malate synthase enzyme similar to that in Mycobacteria, e.g., Mycobacterium tuberculosis.
  • the inhibitory compounds would therefore be effective therapeutics against pathophysiological conditions associated with these bacteria, particularly associated with a malate synthase activity.
  • a therapeutic regimen for these pathophysiological conditions would also comprise administering one or more times, either concurrently or consecutively, one or more other drugs effective against the pathophysiological condition.
  • malate synthase Recombinant full-length malate synthase (or GIcB) enzyme is expressed and purified as previously disclosed ( 1).
  • the structure of malate synthase complexed to the substrate glyoxylate at 2.1 A resolution and the structure with malate and CoA at 2.7 A resolution have been described (1).
  • the structure is a TIM barrel fold for the active site- containing domain and a second _-rich domain of unknown function.
  • malate synthase has a relatively deep and narrow active site (Fig. 2) that extends about 20 A from the surface of the protein to the bound Mg +2 in the bottom of the active site (shown as a blue sphere). This long deep channel binds atoms of the other substrate, CoA.
  • a co-crystal structure of malate synthase complexed with 4-phenyl-2,4- diketobutanoic acid has also been completed.
  • the inhibitor identified through an initial focused screen has an IC 50 of 4.0 ⁇ M. Crystals of the complex were obtained after preincubation of a 3-fold molar excess of inhibitor with the protein.
  • the structure shows that the carboxylate moiety is in contact with the bound Mg +2 , similar to the coordination by such groups in glyoxylate and malate, the two keto oxygens face Arg-339 in a coplanar way, and the phenyl group overlaps the CoA binding site, specifically, the hydrophobic part of the channel that binds the pantothenic tail.
  • the diketo-acid functionality resembles a number of inhibitors of HIV-I integrase (2), which proposedly utilizes carboxy- and carbonyl-oxygens to coordinate two catalytic Mg +2 in the active site.
  • Recombinant Mtb malate synthase with bound inhibitors are produced, purified, and crystallized using full length and truncated forms of the enzyme.
  • the structures and inhibition constants for the full length and truncated enzymes are compared in order to validate the truncated malate synthase for further studies.
  • 5 other truncated forms of the enzyme are designed in order to try to define the best form of the enzyme to take forward for routine structural studies, i.e. better-diffracting, and inhibition assays.
  • Truncated malate synthase expression and purification A C-terminal truncated form of Mtb malate synthase diffracts to higher resolution than the full length protein. Although it is not yet clear what effect the truncation has on enzyme activity and stability, the crystals appear to be more well-ordered.
  • the truncated gene (encoding residues 1-727) is in the pBH4 plasmid, from Dr. James Remington, University of Oregon. This construct codes for an N-terminal His-tag and a Tobacco-etch virus (TEV) protease cleavage site upstream of the malate synthase sequence.
  • TSV Tobacco-etch virus
  • the purification protocol of truncated malate synthase is very similar to that of the full-length enzyme. The two main differences were that the truncated MLS is expressed at 20 degrees overnight and the His tag is removed by TEV protease cleavage at 4 degrees overnight. The yield is typically about 3.6 mg protein from 1 L culture, equivalent to the full length recombinant protein (Fig. 1).
  • the active site Cys-619 located near the entry portal of the active site access channel, in the wild-type malate synthase enzyme was problematic due to the reactivity of its free thiol sidechain with both oxygen, electrophilic compounds in screening libraries and DTNB. Therefore a C619A mutant, exhibiting >80% of the activity of the wild-type enzyme, was generated. Importantly, inhibitors have nearly identical inhibition constants for wild type and mutant forms of the enzyme, and although the mutant is used in screening, all inhibitors are tested against wild type.
  • Inhibition of GIcB is measured by an assay that monitors the formation of HSCoA in the forward enzymatic reaction.
  • the assay is conducted in 96- or 384 well plates using 100 or 50 ⁇ L overall reaction volumes with 26 nM GIcB being reacted in 20 mM Tris pH 7.5 and 5 mM MgCl 2 . All inhibitors (in 100% DMSO) were added such that the final reaction mixture contained 1% DMSO.
  • Inhibitors were incubated with GIcB in Tris buffer containing MgCl 2 for 20 min at room temperature before adding 0.625 mM acetyl-CoA. The reaction was then initiated by the addition of 1.25 mM glyoxylate.
  • the assay measures the increase in absorbance at 412 nm due to the formation of 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB)-CoA adduct.
  • DTNB is injected with glyoxylate at the reaction initiation.
  • a BMG LABTECH POLARstar OPTIMA plate reader in absorbance mode was used to continuously monitor the reaction for 20 min per well. Reaction with a 1% DMSO solution instead of inhibitor was taken as the uninhibited control. The percent inhibition was calculated by comparing the slope/min values (representing the enzyme velocity) of an inhibitor trial to the uninhibited control.
  • a secondary coupled assay with malate dehydrogenase is generated.
  • Malate dehydrogenase uses NAD + or NADF to convert malate to oxaloacetate, and the conversion of NAD or NADPH can be read using either a spectrophotometric assay, or fluoresence.
  • purified malate dehydrogenase is commercially available from a number of sources (human, porcine, and yeast), of the ones tested the equilibrium of the reaction overwhelmingly favors the production of malate.
  • malate dehydrogenase in an assay it is either coupled to another enzyme the can deplete the oxaloacetate or a source of enzyme is found where the reaction favors the production of oxaloacetate.
  • McKinney Lab is grown on 7H9 media with 0.2% dextrose as it is unable to grow on acetate as a sole carbon source.
  • Mycobacterium smegmatis me 2 155 OgIcBD gel with the M. smegmatis glcB deleted, but complemented with Mycobacterium tuberculosis glcB, also from the McKinney lab, is grown on M9 media supplemented with 0.5% acetate as the strain can utilize both dextrose and acetate.
  • Mycobacterium smegmatis mc 2 4517 over-expressing Mycobacterium tuberculosis glcB on a plasmid, i.e., an "over-expressor" strain is grown on M9+acetate media.
  • Inhibitors of GlcB show a marked reduction of activity. This construct is obtained by incorporation of Mtb malate synthase in an M. smegmatis expression vector which is already used as part of the TB Structural Genomics consortium protein production pipeline.
  • HIC 2 VOOO Mycobacterium tuberculosis vaccine strain with defined RDl and panC deletions from H37RV W.R. Jacobs, Albert Einstein College of Medicine, New York
  • N. Y. is grown on both 7H9+dextrose and M9+acetate media; GlcB is essential on either carbon source.
  • Mycobacterium wild-type H37Rv is grown on both 7H9+dextrose and 7H9+acetate. It is contemplated that GIcB is essential irrespective of carbon source.
  • Inhibitors are dissolved in appropriate solvents (typically DMSO-buffer mixtures) and added directly to the cultures over a range of several concentrations. Isoniazid and streptomycin inhibition experiments are run simultaneously to assure quality control. Growth is measured at 24 and 48 hours by taking OD 600 readings in triplicate. A ten-fold dilution using fresh 7H9 is made when initial optical density readings exceed an absorbance of 1.0. The MIC99 is defined as the concentration of inhibitor that kills 99% of the cultured bacteria. The level of malate synthase expression in the strain is determined and compared to the standard laboratory strain of M. smegmatitis by Western blot analysis.
  • This strain provides a much better read-out of the efficacy of the inhibitors, as it more closely measures the inhibition of the Mtb enzyme. All hits with whole cell activity better than ca. 20 ⁇ M are tested against M. smegmatis mc 2 4517. Overexpression of the target gene should lead to resistance to the compound and thus supports the conclusion that the target is malate synthase. Additionally, all hits are examined for inhibition of ICLl and ICL2, in order determine whether any of the inhibitors have activity against these enzymes as well to determine whether there is overlap in inhibitor activity.
  • a UV -Vis spectrophotometer (Varian Cary 100 Bio) was used for the stability determination. AU of the experiments were performed at room temperature using AB buffer as a blank solution which contained 20 mM of Tris-HCl, 5.0 mM of MgCl 2 and 0.8 mM of EDTA. The pH of the solution was maintained at 7.5. 100 mM solutions for each compound were prepared in AB buffer and stored at room temperature. A spectrum for each compound was recorded at regular time intervals, e.g. at 0 time, 24 hrs, 2 day, etc. For each compound, the absorption maxima was recorded and an extinction coefficient was calculated using the Beer -Lambert Law. The time required for a 50% reduction (half-life; t l/2 ) for each compound was determined.
  • Phenyl keto butanoic acid inhibits GIcB
  • a high resolution ( 1.8 A) crystal structure of wild-type GlcB:PKBA demonstrated bidentate binding of the ketoacid moiety to the active-site Mg +2 , hydrogen- bonding of the ketoacid ketone oxygen and the aryl ketone oxygen to Arg-339, and hydrophobic interactions of the phenyl substituent with Leu-461, Met-515, Thr-517, Cys-619, and Met-631.
  • PKBA derivatives and analogs optimizing the aromatic moiety and the diketo acid framework are synthesized.
  • PKBA Fig. 5
  • a suitable dialkyloxalate in the presence of a base, typically a metal alkoxide or hydride, in a polar solvent such as dimethylformamide or an alcohol to afford the PKBA alkyl ester.
  • the alkyl ester may be hydrolyzed to afford the corresponding diketoacid with a strong acid or base.
  • ⁇ /YAo-alkylacetophenones where the alkyl group is ethyl, n-propyl, and /-propyl, were prepared via the method of Cahiez et al (Org. Lett. 2004, 6, 4395-4398) and then utilized with the below pertinent procedure to prepare the corresponding aryldiketo methyl ester and acid.
  • MIC 3.9 mM on acetate
  • MIC 12.5 mM on glucose
  • Table 1 presents results from the ortho-substituted phenyldiketo acids as inhibitors of the glyoxylate shunt in the M. smegmatis and M. tuberculosis models.
  • Table 2 presents inhibition results from di- and tri -substituted phenyldiketo acids.
  • Tables 3-4 present inhibition results from the meta- and para-substituted phenyldiketo acids as inhibitors of the glyoxylate shunt in the M. smegmatis models.
  • Table 5 presents inhibition results from the substituted 2-thienyldiketo acid against the Mycobacterial models. None of the tested compounds demonstrated affinity for isocitrate lyase.
  • Figs. 6A-6C depict binding of the phenyldiketo acid structure within the active site of the malate synthase enzyme.
  • PKBA failed to show significant whole-cell activity because of a lack of stability in a buffered solution.
  • PKBA was stable in water or DMSO, but unstable in buffer (20 mM TrisHCl, + 5 mM MgCl 2 + 0.8 mM EDTA @ pH 7.5) with a half-life (t 1/2 ) of 3 days.

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Abstract

L'invention concerne des composés d'acide dicéto arylique ou hétéroarylique qui sont efficaces pour inhiber une activité d'une enzyme de malate synthase mycobactérienne ou pour inhiber une activité de malate synthase dans d'autres bactéries comportant cette enzyme. Les composés peuvent être des acides dicéto à substitution phényle, naphtyle ou thiényle et des dérivés carboxylate de ceux-ci. L'invention concerne également des procédés utilisant ces composés inhibiteurs pour traiter la tuberculose ou d'autres états pathophysiologiques associés à une enzyme de malate synthase, et des procédés de conception in silico desdits composés. L'invention  concerne en outre les composés inhibiteurs conçus par ledit procédé. Elle concerne de plus des structures cristallines tridimensionnelles aux rayons X de la malate synthase mycobactérienne formant des complexes avec les composés inhibiteurs. L'invention concerne aussi un procédé de stabilisation d'un acide dicéto aromatique ou hétéroaromatique ou d'un promédicament de celui-ci, ou d'un analogue proche en solution, par la dérivatisation d'au moins la position ortho sur le noyau aromatique.
PCT/US2009/005697 2008-10-20 2009-10-20 Inhibiteurs de la mycobacterium tuberculosis malate synthase, procédés de marquage et utilisations de ceux-ci Ceased WO2010047774A2 (fr)

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EP3110415A4 (fr) * 2014-02-28 2017-12-13 The Texas A & M University System Compositions et méthodes d'inhibition de mycobactéries
US10106574B2 (en) 2015-08-13 2018-10-23 Merck Sharp & Dohme Corp. Cyclic di-nucleotide compounds as sting agonists
US10414747B2 (en) 2016-10-04 2019-09-17 Merck Sharp & Dohme Corp. Benzo[b]thiophene compounds as sting agonists
US10793557B2 (en) 2018-04-03 2020-10-06 Merck Sharp & Dohme Corp. Sting agonist compounds
US11285131B2 (en) 2017-08-04 2022-03-29 Merck Sharp & Dohme Corp. Benzo[b]thiophene STING agonists for cancer treatment
US11312772B2 (en) 2017-08-04 2022-04-26 Merck Sharp & Dohme Corp. Combinations of PD-1 antagonists and benzo [b] thiophene STING agonists for cancer treatment
US11453697B1 (en) 2015-08-13 2022-09-27 Merck Sharp & Dohme Llc Cyclic di-nucleotide compounds as sting agonists
US11466047B2 (en) 2017-05-12 2022-10-11 Merck Sharp & Dohme Llc Cyclic di-nucleotide compounds as sting agonists
US11685761B2 (en) 2017-12-20 2023-06-27 Merck Sharp & Dohme Llc Cyclic di-nucleotide compounds as sting agonists
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CA2333707A1 (fr) 1998-06-03 1999-12-09 Melissa Egbertson Inhibiteurs de vih integrase
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CN103420894A (zh) * 2012-05-22 2013-12-04 中国科学院上海药物研究所 丁-2-烯-1,4-二酮类化合物及其制备方法和用途
EP3110415A4 (fr) * 2014-02-28 2017-12-13 The Texas A & M University System Compositions et méthodes d'inhibition de mycobactéries
US10300071B2 (en) 2014-02-28 2019-05-28 The Texas A&M University System Compositions and methods for inhibition of mycobacteria
US10759825B2 (en) 2015-08-13 2020-09-01 Merck Sharp & Dohme Corp. Cyclic di-nucleotide compounds as STING agonists
US10106574B2 (en) 2015-08-13 2018-10-23 Merck Sharp & Dohme Corp. Cyclic di-nucleotide compounds as sting agonists
US11453697B1 (en) 2015-08-13 2022-09-27 Merck Sharp & Dohme Llc Cyclic di-nucleotide compounds as sting agonists
US10766919B2 (en) 2015-08-13 2020-09-08 Merck Sharp & Dohme Corp. Cyclic di-nucleotide compounds as sting agonists
US10738074B2 (en) 2015-08-13 2020-08-11 Merck Sharp & Dohme Corp. Cyclic di-nucleotide compounds as STING agonists
US10414747B2 (en) 2016-10-04 2019-09-17 Merck Sharp & Dohme Corp. Benzo[b]thiophene compounds as sting agonists
US10730849B2 (en) 2016-10-04 2020-08-04 Merck Sharp & Dohme Corp. Benzo[b]thiophene compounds as STING agonists
US10703738B2 (en) 2016-10-04 2020-07-07 Merck Sharp & Dohme Corp. Benzo[b]thiophene compounds as STING agonists
US11466047B2 (en) 2017-05-12 2022-10-11 Merck Sharp & Dohme Llc Cyclic di-nucleotide compounds as sting agonists
US11285131B2 (en) 2017-08-04 2022-03-29 Merck Sharp & Dohme Corp. Benzo[b]thiophene STING agonists for cancer treatment
US11312772B2 (en) 2017-08-04 2022-04-26 Merck Sharp & Dohme Corp. Combinations of PD-1 antagonists and benzo [b] thiophene STING agonists for cancer treatment
US11685761B2 (en) 2017-12-20 2023-06-27 Merck Sharp & Dohme Llc Cyclic di-nucleotide compounds as sting agonists
US10793557B2 (en) 2018-04-03 2020-10-06 Merck Sharp & Dohme Corp. Sting agonist compounds
US11702430B2 (en) 2018-04-03 2023-07-18 Merck Sharp & Dohme Llc Aza-benzothiophene compounds as STING agonists

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